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Mysterious case of patient with 12 tumors revealed

Scientists at the Spanish National Cancer Research Center (CNIO) have described a mysterious case of a female patient who developed 12 different tumors in different parts of her body over the course of 40 years, five of which were malignant. An article that reveals the cause of an abnormal disease was published in the journal Science Advances. Briefly about the results of scientific research is described in a press release on MedicalXpress.

At the age of two years, the patient, born in 1986, was diagnosed with stage III fetal rhabdomyosarcoma of the left ear canal, which was treated with chemotherapy and radiation therapy. In 2001, several bony lesions were seen in the femur, humerus, and ulna. In the same year, doctors discovered clear cell carcinoma of the cervix, which required surgery and radiation therapy. In 2006, the patient had an adenoma of the left parotid gland removed, and a year later, a fusiform sarcoma. From 2006 to 2010, doctors removed several nevi, a breast lipoma, and a pilomatricoma. In addition, the woman developed such tumors as colon adenoma with adenocarcinoma, rectal adenocarcinoma, tubular adenomas and nodular goiter.

Whole genome sequencing of the patient showed that she has mutations in both copies of the MAD1L1 gene, which lead to premature termination of transcription. MAD1L1 encodes a protein that is involved in the correct segregation of chromosomes during cell division (mitosis), so mutations contribute to frequent aneuploidy – a situation where the wrong number of chromosomes appear in cells. The most common were three copies (instead of two) of the 21st chromosome, as well as extra copies of the 12th and 18th chromosomes. In some cases, chromosome loss has been observed. At the same time, the most pronounced changes in chromosomes occurred in the tissues of malignant tumors.

Animal model studies have shown that mutations affecting both copies of the MAD1L1 gene are fatal to the developing embryo. This makes the patient’s case extremely unusual: not only did she survive, but she lives a relatively full life, as one would expect from a person in poor health, does not suffer from microcephaly or mental retardation. Other cases of mutations leading to chromosomal instability are known, but they are less aggressive in terms of the risk of developing tumors, but at the same time cause significant cognitive impairment.

The patient’s organism relatively easily coped with malignant neoplasms. The hypothesis of the researchers is that permanent disturbances in the number of chromosomes played against the progression of tumors, preventing the appearance of metastases. So, aneuploidy affected T-lymphocytes, in which the number of copies of the 18th chromosome increased. These cells synthesized an increased amount of substances, indicating increased cytotoxicity, that is, the ability to destroy defective cells.

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